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Phospholipase C;1 Is Required for Metastasis Development and Progression

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Phospholipase C;1 Is Required for Metastasis Development and Progression Research Article Phospholipase C;1 Is Required for Metastasis Development and Progression Gianluca Sala,1 Francesco Dituri,1 Claudio Raimondi,1 Sara Previdi,2 Tania Maffucci,1 Marco Mazzoletti,2 Cosmo Rossi,3 Manuela Iezzi,3 Rossano Lattanzio,3 Mauro Piantelli,3 Stefano Iacobelli,3 Massimo Broggini,2 and Marco Falasca1 1Inositide Signalling Group, Centre for Diabetes and Metabolic Medicine, Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, London, United Kingdom; 2Laboratory of Molecular Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy; and 3Center of Excellence on Aging, G. d’Annunzio University Foundation, Chieti, Italy Abstract critical role in both cytoskeletal changes and migration associated g Cell motility and invasion play an essential role in the with the metastatic process (5, 6). Activation of PLC 1 can occur in development of metastasis. Evidence suggests that the enzyme response to either growth factors or integrin receptors–dependent phospholipase C;1(PLC;1) may be involved in tumor pathways and induces hydrolysis of phosphatidylinositol-4,5- progression and possibly development of metastasis. In this bisphosphate (PtdIns-4,5-P2) to form the second messengers study, we show that down-regulation of PLC;1 expression diacylglycerol and inositol-1,4,5-trisphosphate, which in turn g severely impairs activation of the small GTP-binding protein activate a number of signaling molecules (7, 8). PLC 1 has been Rac and cell invasion in breast cancer cell lines and U87 shown to play a critical role in cell migration, invasion, and g in vitro. Experimental metastasis assays in nude mice show spreading (9–12). Indeed, PLC 1 is highly expressed in several tumors, such as breast carcinomas, and in highly metastatic that inducible knockdown of PLC;1 strongly inhibits deve- lopment of MDA-MB-231–derived lung metastasis and reverts colorectal tumor cell lines (13, 14). In particular, we showed g metastasis formation. In addition, analysis of 60 breast cancer previously that phosphoinositide 3-kinase (PI3K)–mediated PLC 1 patients’ tissues revealed an increase of PLC;1 expression activation is required for epidermal growth factor (EGF)–induced g in metastasis compared with the primary tumor in 50% of migration of breast cancer cells (15) but the mechanism of PLC 1- tissues analyzed. These data showa critical role of PLC; 1in dependent cell migration and metastasis was not clearly defined. g the metastatic potential of cancer cells, and they further Although previous studies provide evidences that PLC could be indicate that PLC;1 inhibition has a therapeutic potential in involved in carcinoma invasion, it should be noted that this the treatment of metastasis dissemination. [Cancer Res observation was based on the use of generic PLC chemical g 2008;68(24):10187–96] inhibitor (11) or dominant-negative PLC (16). Here, we investigate the role of PLCg1 in cell invasion and metastasis using different approaches to modulate PLCg1 expression in highly invasive Introduction cancer cell lines. Our results show that PLCg1 is required for breast Metastasis, the ability of cancer cells to spread from a primary cancer cell invasion and Rac1 activation. These data reveal a site and form tumors at distant sites, is the main cause of death functional link between PLCg1 and Rac1 that provides insight into associated with cancer. Several steps regulate the development of processes regulating cell invasion. Furthermore, we show that metastasis (local invasion, intravasation, survival, extravasation, down-regulation of PLCg1 expression inhibits the human breast initiation, and maintenance of micrometastases at distant sites and cancer cell line MDA-MB-231–derived lung metastasis develop- vascularization of the resulting tumors). Cell motility and invasion ment in in vivo mice model. According to this, immunohistochem- plays an essential role in such a process, and identification of ical analysis of tissues derived from breast cancer patients shows molecules and characterization of the mechanisms regulating cell an increase of PLCg1 expression in metastasis compared with the motility is critical to understand metastasis development (1–4). primary tumor in around 50% of tissues analyzed. These data show Directed cell migration is regulated by chemokines and growth that PLCg1 is necessary for breast cancer–derived metastasis factors that bind and activate specific receptors, such as receptor development. Moreover, we show that inducible down-regulation of tyrosine kinases. Receptors convert these outside signals to activate PLCg1 expression after 14 days of injection of MDA-MB-231 in a complex network of intracellular pathways that regulate cell nude mice is able to revert metastasis formation, indicating that cytoskeleton rearrangement and motility. In this regard, activation blockade of PLCg1 has a therapeutic potential to counteract of the enzyme phospholipase Cg1 (PLCg1) is thought to play a metastasis dissemination. Note: Supplementary data for this article are available at Cancer Research Online Materials and Methods (http://cancerres.aacrjournals.org/). Materials and constructs. Sequence targeting the human PLCg1 mRNA Current address for G. Sala: Laboratory of Molecular Oncology, Center of was subcloned into pSuper and pSuperior vectors (ref. 17; Supplementary Excellence on Aging, G. d’Annunzio University Foundation, Chieti, Italy. B Requests for reprints: Marco Falasca, Inositide Signalling Group, Centre for Fig. S1 ). Control vectors (pSuper 3Mut and pSuperior 3Mut) contain a Diabetes and Metabolic Medicine, Institute of Cell and Molecular Science, Barts and three-point mutated sequence unable to target the human PLCg1 mRNA The London School of Medicine and Dentistry, Queen Mary, University of London, 4 (Supplementary Fig. S1B). Palm-HA-PLCg1 was kindly provided by Dr. E. Newark Street, London E1 2AT, United Kingdom. Phone: 44-0-20-7882-8243; Fax: 44-0- Bonvini (MacroGenics, Inc.). Antibodies were as follows: phosphorylated 20-7882-2186; E-mail: [email protected]. 783 I2008 American Association for Cancer Research. PLCg1(Tyr ), PLCg1, phosphorylated epidermal growth factor receptor doi:10.1158/0008-5472.CAN-08-1181 (EGFR; Tyr992), EGFR, phosphorylated AKT (Ser473), AKT, phosphorylated www.aacrjournals.org 10187 Cancer Res 2008; 68: (24). December 15, 2008 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2008 American Association for Cancer Research. Cancer Research extracellular signal-regulated kinases (ERK), and ERKs from Cell Signaling; temperature and blocked with 0.1% bovine serum albumin for 30 min at phosphorylated focal adhesion kinase (FAK; Tyr397) from BioSource; Rac1, room temperature. Coverslips were then incubated for 2 h at room FAK, paxillin, and glyceraldehyde-3-phosphate dehydrogenase from Santa temperature with the appropriate primary antibody (antipaxillin, anti-FAK Cruz Biotechnology; phosphorylated Tyr (4G10) from UBI; and CD44 from antibodies). Rhodamine-labeled phalloidin was used to visualize actin Novocastra Laboratories Ltd. cytoskeleton. Confocal imaging was performed using a BIO-RAD Radiance Cell culture, transfection, and RNA interference. MDA-MB-231 and 2100 laser and an upright Nikon Eclipse E1000 microscope running U87 cells were grown in DMEM; MDA-MB-435 and TSA were grown in LaserSharp 2000 software. Ruffles formation was assessed as described (21). RPMI. Media were supplemented with 10% fetal bovine serum (FBS), Animals. Female nude athymic CD-1 nu/nu mice (7 wk old) and BALB/c sodium pyruvate, penicillin, and streptomycin and incubated in 5% CO2 at mice were purchased from Charles River Laboratories and maintained 37jC. TSA is an aggressive and poorly immunogenic cell line established under specific pathogen-free conditions with food and water provided ad from a moderately differentiated mammary adenocarcinoma that arose libitum. The general health status of the animals was monitored daily. spontaneously in a multiparous BALB/c mouse. Procedure involving animals and their care were conducted in conformity Down-regulation of PLCg1 was obtained by using pSuper retro and with the institutional guidelines that are in compliance with national and pSuperior retro–based vectors to express stable or inducible short hairpin international laws and policies. RNA (shRNA), respectively. Retroviral stocks were generated as described Experimental lung metastasis assay. Control (3Mut) and inducible/ (18). For the inducible system, down-regulation of PLCg1 expression was stable PLCg1 knockdown MDA-MB-231 cells were injected into the tail vein obtained by culturing cells in medium containing 2 Ag/mL doxycycline of recipient mice (2 Â 106 per mouse). Five weeks after cell implant/ (Sigma) or 10 Ag/mL tetracycline (Sigma). MDA-MB-231 stable cell lines injection, lung tissues (five lungs per group) were excised and immediately expressing the membrane-associated, palmitoylated HA-tagged PLCg1 were fixed in 10% neutral buffered formalin. Lungs were then embedded in transfected with 5 Ag of palmitoylated HA-tagged PLCg1 (Palm-PLCg-1-HA) paraffin, and thick sections (10 Am; two sections per lung tissue) were cut using Lipofectamine 2000 (Invitrogen) and then selected with 500 Ag/mL and stained with H&E or with an anti-CD44 monoclonal antibody from of G418. Santa Cruz Biotechnology. Rac1 activation assay. For EGF stimulation, 2 Â 106 cells plated in In vivo tumor growth. pSuperior 3Mut and shPLCg1 MDA-MB-231 cells 10-cm dishes were serum starved for 24 h and then stimulated with were injected s.c. into the left and right flanks of each mouse, respectively 20 ng/mL EGF (Sigma) for 5 min. For serum growing condition, 1 Â 106 cells (6 Â 106 per mouse). When tumors reached a size of f50 mm3, mice were were plated in 10-cm dishes and allowed to grow for 3 d in the absence or randomized in two groups (n = 5), with one group receiving tetracycline presence of doxycycline to down-regulate PLCg1 expression. Cells were (2 mg/mL; Sigma) in drinking water. Tetracycline was replaced every 2 d. then lysed on ice in lysis buffer [50 mmol/L Tris (pH 7.2), 100 mmol/L NaCl, The diameter of s.c.
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